Abstract

Abstract Two compounds with high affinity for the “peripheral type” benzodiazepine binding sites, PK 11195 (an isoquinoline derivative) and R05-4864 (a benzodiazepine derivative) can modify the sensitivity of DBA/2J mice to audiogenic seizures. R05-4864 (1–15 mg/kg) facilitates in a dose-dependent manner the audiogenic seizures and PK 11195 (2–5 mg/kg) antagonizes the R05-4864 effects. At these doses PK 11195 alone does not modify the sensitivity to audiogenic seizures, but at doses between 20–80 mg/kg it protects DBA/2J mice againts audiogenic seizures. By contrast PK 11195 is inactive againts the facilitation of audiogenic seizures by ethyl-β-carboline-3-carboxylate (a brain benzodiazepine receptor inverse agonist) and againts the seizure elicited in absence of noise stimuli by R05-4864 at doses between 20–40 mg/kg. These results suggest that facilitation by R05-4864 of the audiogenic seizures and its antagonism by PK 11195 are mediated by the peripheral type benzodiazepine binding sites and agree with the thermodynamic analysis of the binding data which suggested that R05-4864 might be an agonist and PK 11195 an antagonist. The good correlation between pharmacological effects and the occupancy degree of the binding sites as measured by the displacement of the “in vivo” [ 3H]-PK 11195 binding give an additional support to binding sites mediated effects.

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